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Serge Van Calenbergh - One of the best experts on this subject based on the ideXlab platform.
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synthesis and evaluation of 5 modified Thymidines and 5 hydroxymethyl 2 deoxyuridines as mycobacterium tuberculosis thymidylate kinase inhibitors
Bioorganic & Medicinal Chemistry, 2013Co-Authors: Kiran S Toti, Frederick Verbeke, Martijn Risseeuw, Vladimir Frecer, Helene Munierlehmann, Serge Van CalenberghAbstract:We report the synthesis of 5'-modified Thymidines (16, 18, 21, 23) and 5,5'-bis-substituted 2'-deoxyuridine analogues (30, 47) as inhibitors of Thymidine Monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). These analogues were evaluated for their capacity to inhibit TMPKmt and solely two 5'-modified Thymidines were found to possess moderate inhibitory activity. In addition, a feasibility study of protecting groups for the 5-CH(2)OH moiety of 2'-deoxyuridines is described that enables to introduce the desired 5'-modification.
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Synthesis and inhibitory activity of Thymidine analogues targeting Mycobacterium tuberculosis Thymidine Monophosphate kinase.
Bioorganic and Medicinal Chemistry, 2011Co-Authors: Sara Van Poecke, Hélène Munier-lehmann, Matheus Froeyen, Olivier Helynck, Serge Van CalenberghAbstract:We report on Mycobacterium tuberculosis Thymidine Monophosphate kinase (TMPKmt) inhibitory activities of a series of new 3'- and 5'-modified Thymidine analogues including α- and β-derivatives. In addition, several analogues were synthesized in which the 4-oxygen was replaced by a more lipophilic sulfur atom to probe the influence of this modification on TMPKmt inhibitory activity. Several compounds showed an inhibitory potency in the low micromolar range, with the 5'-arylthiourea 4-thio-α-Thymidine analogue being the most active one (K(i)=0.17μM). This compound was capable of inhibiting mycobacteria growth at a concentration of 25μg/mL.
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From M-tuberculosis Thymidine Monophosphate kinase (TMPKmt) inhibitors towards mitochondrial Thymidine kinase (TK-2) inhibitors
Collection Symposium Series, 2008Co-Authors: Serge Van Calenbergh, Matheus Froeyen, Ineke Van Daele, Sara Van Poecke, Hélene Munier Lehmann, Jan BalzariniAbstract:Here, we report on the enzyme structure-aided design of a series of substituted 3'- or 5'-thiourea derivatives of beta- and alpha-Thymidine, respectively, as Thymidine Monophosphate kinase inhibitors of M. tuberculosis. In a recent study, several 3'-thiourea substituted Thymidine derivatives were found to be exquisitely potent and specific inhibitors of mitochondrial Thymidine kinase (TK-2), with high selectivity when compared with cytosolic TK-1.
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rational design of 5 thiourea substituted α Thymidine analogues as Thymidine Monophosphate kinase inhibitors capable of inhibiting mycobacterial growth
Journal of Medicinal Chemistry, 2007Co-Authors: Ineke Van Daele, Helene Munierlehmann, Matheus Froeyen, Jan Balzarini, Serge Van CalenberghAbstract:Recently, Thymidine Monophosphate kinase (TMPK) emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. The elucidation of the X-ray structure of TMPK of M. tuberculosis (TMPKmt), as well as the structure of an earlier serendipitously discovered dimeric Thymidine inhibitor, laid the foundation for the design of potent and selective TMPKmt inhibitors reported here. Several hits identified within a series of 3'-C-branched thiourea-substituted beta-Thymidine derivatives inspired us to construct a set of 5'-thiourea-substituted alpha-Thymidine derivatives characterized by a similar relative orientation of the thymine and arylthiourea moieties. alpha-Thymidine derivative 15, featuring a (3-trifluoromethyl-4-chlorophenyl)thiourea moiety, has a Ki of 0.6 microM and a selectivity index of 600 versus human TMPK. Moreover, it represents the first TMPK inhibitor showing good inhibitory activity on growing M. bovis (MIC99 = 20 microg/mL) and M. tuberculosis (MIC50 = 6.25 microg/mL) strains.
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synthesis and biological evaluation of bicyclic nucleosides as inhibitors of m tuberculosis thymidylate kinase
ChemMedChem, 2006Co-Authors: Ineke Van Daele, Helene Munierlehmann, Matheus Froeyen, Pieter Hendrickx, G Marchal, P Chavarot, Li Qing, Jose C Martins, Serge Van CalenberghAbstract:Herein we describe the synthesis and conformational analysis of a series of bicyclic Thymidine derivatives and their evaluation as inhibitors of Thymidine Monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), based on previously discovered bicyclic sugar nucleosides. With a K(i) value of 2.3 microm, 1-[3-aminomethyl-3,5-dideoxy-2-O,6-N-(thiocarbonyl)-beta-D-ribofuranosyl]thymine emerged as the most potent TMPK inhibitor of this series. Moreover, this promising compound displays inhibitory potency against Mycobacteria cultures with an IC(99) value of 100 microg mL(-1), thus promoting TMPKmt for the first time as a validated target for further inhibitory design. Attempts to rationalise the observed structure-activity relationship (SAR) involving molecular modelling and conformational analysis are described.
Helene Munierlehmann - One of the best experts on this subject based on the ideXlab platform.
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synthesis and evaluation of 5 modified Thymidines and 5 hydroxymethyl 2 deoxyuridines as mycobacterium tuberculosis thymidylate kinase inhibitors
Bioorganic & Medicinal Chemistry, 2013Co-Authors: Kiran S Toti, Frederick Verbeke, Martijn Risseeuw, Vladimir Frecer, Helene Munierlehmann, Serge Van CalenberghAbstract:We report the synthesis of 5'-modified Thymidines (16, 18, 21, 23) and 5,5'-bis-substituted 2'-deoxyuridine analogues (30, 47) as inhibitors of Thymidine Monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). These analogues were evaluated for their capacity to inhibit TMPKmt and solely two 5'-modified Thymidines were found to possess moderate inhibitory activity. In addition, a feasibility study of protecting groups for the 5-CH(2)OH moiety of 2'-deoxyuridines is described that enables to introduce the desired 5'-modification.
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design synthesis and inhibitory activity against mycobacterium tuberculosis Thymidine Monophosphate kinase of acyclic nucleoside analogues with a distal imidazoquinolinone
ChemInform, 2011Co-Authors: Olga Familiar, Helene Munierlehmann, Jose A Ainsa, Mariajose Camarasa, Mariajesus PerezperezAbstract:New acyclic analogues, structurally related to previously described acyclic nucleoside inhibitors, are synthesized via PIFA-mediated electrocyclization of N-methoxyureas, e.g. (V), followed by elimination of the methoxy groups by catalytic hydrogenation.
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design synthesis and inhibitory activity against mycobacterium tuberculosis Thymidine Monophosphate kinase of acyclic nucleoside analogues with a distal imidazoquinolinone
European Journal of Medicinal Chemistry, 2010Co-Authors: Olga Familiar, Helene Munierlehmann, Jose A Ainsa, Mariajose Camarasa, Mariajesus PerezperezAbstract:Thymidine Monophosphate kinase from Mycobacterium tuberculosis (TMPKmt) has been proposed as an attractive target in the search of new agents to fight against tuberculosis. We recently reported that thymine derivatives carrying a naphtholactam or naphthosultam moiety at position 4 of a (Z)-butenyl chain inhibit TMPKmt in the subμM range. Here we describe the replacement of the planar naphtholactam and naphthosultam rings in our identified hits by 5,6-dihydro-1H-imidazo[4,5,1-ij]quinolinones and a 5,6-dihydro-1H,4H-1,2,5-thiadiazolo[4,3,2-ij]quinoline-2,2-dioxide where the planarity has been broken. Interestingly, these non-planar compounds were similarly potent against the target enzyme than their aromatic analogues, suggesting a bioisosteric behavior that may also be applied to other biologically active compounds. The synthesis of the different targeted imidazoquinolinones has been successfully performed via a hypervalent iodide mediated oxidative cyclization of N-methoxyureas catalized by bis(trifluoroacetoxy)iodobenzene (PIFA) expanding the reported use of this reagent for the synthesis of differently substituted imidazoquinolinones.
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exploring acyclic nucleoside analogues as inhibitors of mycobacterium tuberculosis thymidylate kinase
ChemMedChem, 2008Co-Authors: Olga Familiar, Helene Munierlehmann, Mariajose Camarasa, Ana Negri, Federico Gago, Dominique Douguet, Leen Rigouts, Anaisabel Hernandez, Mariajesus PerezperezAbstract:In the search for novel inhibitors of the enzyme Thymidine Monophosphate kinase of Mycobacterium tuberculosis (TMPKmt), an attractive target for novel antituberculosis agents, we report herein the discovery of the first acyclic nucleoside analogues that potently and selectively inhibit TMPKmt. The most potent compounds in this series are (Z)-butenylthymines carrying a naphtholactam or naphthosultam moiety at position 4, which display K(i) values of 0.42 and 0.27 microM, respectively. Docking studies followed by molecular dynamics simulations performed to rationalize the interaction of this new family of inhibitors with the target enzyme revealed a key interaction between the distal substituent and Arg 95 in the target enzyme. The fact that these inhibitors are more easily synthesizable than previously identified TMPKmt inhibitors, together with their potency against the target enzyme, makes them attractive lead compounds for further optimization.
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a new family of inhibitors of mycobacterium tuberculosis Thymidine Monophosphate kinase
ChemInform, 2008Co-Authors: Cécile Gasse, Helene Munierlehmann, Dominique Douguet, Valérie Huteau, Sylvie PochetAbstract:Tuberculosis (TB) ranks among the leading causes of death worldwide from a single infectious agent, particularly in developing countries. The emergence of multidrug resistant strains of Mycobacteri...
Piet Herdewijn - One of the best experts on this subject based on the ideXlab platform.
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substrate dependence of competitive nucleotide pyrophosphatase phosphodiesterase1 npp1 inhibitors
Frontiers in Pharmacology, 2017Co-Authors: Soumya Sarkar, Sanjay Bhattarai, Vigneshwaran Namasivayam, Ali Eltayeb, Holger Stephan, Steven De Jonghe, Piet Herdewijn, Christa E. MüllerAbstract:Nucleotide pyrophosphatase / phosphodiesterase type 1 (NPP1) is a membrane glycoprotein involved in the hydrolysis of extracellular nucleotides. Its major substrate is ATP which is converted to AMP and diphosphate. NPP1 was proposed as a new therapeutic target in brain cancer and immuno-oncology. Several NPP1 inhibitors have been reported to date, most of which were evaluated versus the artificial substrate p-nitrophenyl 5’-Thymidine Monophosphate (p-Nph-5’-TMP). Recently, we observed large discrepancies in inhibitory potencies for a class of competitive NPP1 inhibitors when tested versus the artificial substrate p-Nph-5’-TMP as compared to the natural substrate ATP. Therefore, the goal of the present study was to investigate whether inhibitors of human NPP1 generally display substrate-dependent inhibitory potency. Systematic evaluation of nucleotidic as well as non-nucleotidic NPP1 inhibitors revealed significant differences in determined Ki values for competitive, but not for non- and un-competitive inhibitors when tested versus the frequently used artificial substrate p-Nph-5’-TMP as compared to ATP. Allosteric modulation of NPP1 by p-Nph-5’-TMP may explain these discrepancies. Results obtained using the AMP derivative p-nitrophenyl 5’-adenosine Monophosphate (p-Nph-5’-AMP) as an alternative artificial substrate correlated much better with those employing the natural substrate ATP.
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imidazopyridine and purine thioacetamide derivatives potent inhibitors of nucleotide pyrophosphatase phosphodiesterase 1 npp1
Journal of Medicinal Chemistry, 2014Co-Authors: Lei Chang, Piotr Leonczak, Theodor Hanck, Christa E. Müller, Steven De Jonghe, Jef Rozenski, Piet HerdewijnAbstract:Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) belongs to the family of ecto-nucleotidases, which control extracellular nucleotide, nucleoside, and (di)phosphate levels. To study the (patho)physiological roles of NPP1 potent and selective inhibitors with drug-like properties are required. Therefore, a compound library was screened for NPP1 inhibitors using a colorimetric assay with p-nitrophenyl 5′-Thymidine Monophosphate (p-Nph-5′-TMP) as an artificial substrate. This led to the discovery of 2-(3H-imidazo[4,5-b]pyridin-2-ylthio)-N-(3,4-dimethoxyphenyl)acetamide (5a) as a hit compound with a Ki value of 217 nM. Subsequent structure–activity relationship studies led to the development of purine and imidazo[4,5-b]pyridine analogues with high inhibitory potency (Ki values of 5.00 nM and 29.6 nM, respectively) when assayed with p-Nph-5′-TMP as a substrate. Surprisingly, the compounds were significantly less potent when tested versus ATP as a substrate, with Ki values in the low micromolar range. A prot...
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Synthesis and evaluation of 6-aza-2'-deoxyuridine Monophosphate analogs as inhibitors of thymidylate synthases, and as substrates or inhibitors of Thymidine Monophosphate kinase in Mycobacterium tuberculosis.
Chemistry and Biodiversity, 2012Co-Authors: Martin Kögler, Steven De Jonghe, Jef Rozenski, Hélène Munier-lehmann, Roger Busson, Kristien Van Belle, Thierry Louat, Piet HerdewijnAbstract:A series of 5-substituted analogs of 6-aza-2'-deoxyuridine 5'-Monophosphate, 6-aza-dUMP, has been synthesized and evaluated as potential inhibitors of the two mycobacterial thymidylate synthases (i.e., a flavin-dependent thymidylate synthase, ThyX, and a classical thymidylate synthase, ThyA). Replacement of C(6) of the natural substrate dUMP by a N-atom in 6-aza-dUMP 1a led to a derivative with weak ThyX inhibitory activity (33% inhibition at 50 μM). Introduction of alkyl and aryl groups at C(5) of 1a resulted in complete loss of inhibitory activity, whereas the attachment of a 3-(octanamido)prop-1-ynyl side chain in derivative 3 retained the weak level of mycobacterial ThyX inhibition (40% inhibition at 50 μM). None of the synthesized derivatives displayed any significant inhibitory activity against mycobacterial ThyA. The compounds have also been evaluated as potential inhibitors of mycobacterial Thymidine Monophosphate kinase (TMPKmt). None of the derivatives showed any significant TMPKmt inhibition. However, replacement of C(6) of the natural substrate (dTMP) by a N-atom furnished 6-aza-dTMP (1b), which still was recognized as a substrate by TMPKmt.
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Discovery of bicyclic Thymidine analogues as selective and high-affinity inhibitors of Mycobacterium tuberculosis Thymidine Monophosphate kinase.
Journal of Medicinal Chemistry, 2004Co-Authors: Veerle Vanheusden, Jef Rozenski, Piet Herdewijn, Hélène Munier-lehmann, Matheus Froeyen, Roger Busson, Serge Van CalenberghAbstract:Thymidine Monophosphate kinase of Mycobacterium tuberculosis (TMPKmt) represents an attractive target for selectively blocking bacterial DNA synthesis. Hereby, we report on the discovery of a novel class of bicyclic nucleosides (10 and 11) and one dinucleoside (12), belonging to the most selective inhibitors of TMPKmt discovered so far.
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Thymidine and Thymidine 5 o Monophosphate analogues as inhibitors of mycobacterium tuberculosis thymidylate kinase
Bioorganic & Medicinal Chemistry Letters, 2003Co-Authors: Veerle Vanheusden, Piet Herdewijn, Helene Munierlehmann, Sylvie Pochet, Philippe Van Rompaey, Serge Van CalenberghAbstract:The affinity of a series of 2', 3'- and 5-modified Thymidine analogues for Mycobacterium tuberculosis Thymidine Monophosphate kinase (TMPKmt) was evaluated. The affinities of several non-phosphorylated analogues are in the same order of magnitude as those of their phosphorylated congeners. In view of drug delivery problems associated with phosphorylated compounds, these 'free' nucleosides seem more promising leads in the search of TMPKmt inhibitors as novel anti-tuberculosis agents.
Hélène Munier-lehmann - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of sulfamide analogues of deoxThymidine Monophosphate as potential inhibitors of mycobacterial cell wall biosynthesis
Carbohydrate Research, 2018Co-Authors: Kajitha Suthagar, Wanting Jiao, Hélène Munier-lehmann, Antony FairbanksAbstract:The recently discovered enzyme Mycobacterium tuberculosis Thymidine Monophosphate kinase (TMPKmt), which catalyses the phosphorylation of deoxyThymidine Monophosphate (dTMP) to give deoxyThymidine diphosphate (dTDP), is indispensable for the growth and survival of M. tuberculosis as it plays an essential role in DNA synthesis. Inhibition of TMPKmt is an attractive avenue for the development of novel anti-tuberculosis agents. Based on the premise that sulfamide may be a suitable isostere of phosphate, deoxyThymidine analogues comprising various substituted sulfamides at C5′ were modelled in silico into the active site of TMPKmt (PDB accession code: 1N5K) using induced-fit docking methods. A selection of modelled compounds was synthesized, and their activity as inhibitors of TMPKmt was evaluated. Three compounds showed competitive inhibition of TMPKmt in the micromolar range (10–50 μM). Compounds were tested in vitro for anti-mycobacterial activity against M. smegmatis: three compounds showed weak anti-mycobacterial activity (MIC 250 μg/mL).
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Tetrahydro-2-furanyl-2,4(1H,3H)-pyrimidinedione derivatives as novel antibacterial compounds against Mycobacterium
Wolters Kluwer Medknow Publications, 2017Co-Authors: Yuji Koseki, Hélène Munier-lehmann, Hironori Kanetaka, Joji Tsunosaki, Shunsuke AokiAbstract:Objective/Background: Mycobacterium tuberculosis Thymidine Monophosphate kinase (mtTMPK) is a potential enzymatic target for the treatment of tuberculosis (TB). Materials and Methods: In this study, we performed pharmacophore-based in silico screening, targeting mtTMPK with a compound library of 461,383 chemicals. We evaluated the candidate compounds for inhibitory effects on the growth of the model mycobacteria, Mycobacterium smegmatis. Results: The compound KTP3 completely inhibited the growth of M. smegmatis at 100 μM. A similarity search and rescreening with the structure of compound KTP3 using a web-based database identified two similar compounds (KTPS1 and KTPS2) with improved potency. The KTP3 analogs, KTPS1 and KTPS2, exhibited strong growth inhibitory effects with half-maximal inhibitory concentration values of 8.04 μM and 17.1 μM, respectively, against M. smegmatis. Moreover, the most potent chemical compound, KTPS1, did not exhibit toxic effects on the model enterobacteria and several mammalian cells. Two active chemicals, KTPS1 and KTPS2, inhibited mtTMPK activity by 18% and 36%, respectively, suggesting that these compounds have off-target activities against Mycobacterium. Conclusion: Structural and biological information on these chemicals is likely to be useful for the development of novel antibiotics for the treatment of TB
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Synthesis and evaluation of 6-aza-2'-deoxyuridine Monophosphate analogs as inhibitors of thymidylate synthases, and as substrates or inhibitors of Thymidine Monophosphate kinase in Mycobacterium tuberculosis.
Chemistry and Biodiversity, 2012Co-Authors: Martin Kögler, Steven De Jonghe, Jef Rozenski, Hélène Munier-lehmann, Roger Busson, Kristien Van Belle, Thierry Louat, Piet HerdewijnAbstract:A series of 5-substituted analogs of 6-aza-2'-deoxyuridine 5'-Monophosphate, 6-aza-dUMP, has been synthesized and evaluated as potential inhibitors of the two mycobacterial thymidylate synthases (i.e., a flavin-dependent thymidylate synthase, ThyX, and a classical thymidylate synthase, ThyA). Replacement of C(6) of the natural substrate dUMP by a N-atom in 6-aza-dUMP 1a led to a derivative with weak ThyX inhibitory activity (33% inhibition at 50 μM). Introduction of alkyl and aryl groups at C(5) of 1a resulted in complete loss of inhibitory activity, whereas the attachment of a 3-(octanamido)prop-1-ynyl side chain in derivative 3 retained the weak level of mycobacterial ThyX inhibition (40% inhibition at 50 μM). None of the synthesized derivatives displayed any significant inhibitory activity against mycobacterial ThyA. The compounds have also been evaluated as potential inhibitors of mycobacterial Thymidine Monophosphate kinase (TMPKmt). None of the derivatives showed any significant TMPKmt inhibition. However, replacement of C(6) of the natural substrate (dTMP) by a N-atom furnished 6-aza-dTMP (1b), which still was recognized as a substrate by TMPKmt.
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Drug design and identification of potent leads against Mycobacterium tuberculosis Thymidine Monophosphate kinase.
Current Topics in Medicinal Chemistry, 2012Co-Authors: S. Van Calenbergh, Sylvie Pochet, Hélène Munier-lehmannAbstract:Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases impeding DNA synthesis. In contrast, nucleoside analogues are much less explored as antibacterial drugs. Thymidine Monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), which is essential to DNA replication, was selected as a promising target for the design of new inhibitors. This review describes stepwise modifications of the TMPKmt substrate, guided by the feedback of enzyme assays and crystallographic analysis to afford potent enzyme inhibitors some of which also exhibited antitubercular activity. More importantly, several of the reported Thymidine analogues provided a deeper understanding of the structure and catalytic mechanism of this intriguing enzyme.
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Synthesis and inhibitory activity of Thymidine analogues targeting Mycobacterium tuberculosis Thymidine Monophosphate kinase.
Bioorganic and Medicinal Chemistry, 2011Co-Authors: Sara Van Poecke, Hélène Munier-lehmann, Matheus Froeyen, Olivier Helynck, Serge Van CalenberghAbstract:We report on Mycobacterium tuberculosis Thymidine Monophosphate kinase (TMPKmt) inhibitory activities of a series of new 3'- and 5'-modified Thymidine analogues including α- and β-derivatives. In addition, several analogues were synthesized in which the 4-oxygen was replaced by a more lipophilic sulfur atom to probe the influence of this modification on TMPKmt inhibitory activity. Several compounds showed an inhibitory potency in the low micromolar range, with the 5'-arylthiourea 4-thio-α-Thymidine analogue being the most active one (K(i)=0.17μM). This compound was capable of inhibiting mycobacteria growth at a concentration of 25μg/mL.
Sylvie Pochet - One of the best experts on this subject based on the ideXlab platform.
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Drug design and identification of potent leads against Mycobacterium tuberculosis Thymidine Monophosphate kinase.
Current Topics in Medicinal Chemistry, 2012Co-Authors: S. Van Calenbergh, Sylvie Pochet, Hélène Munier-lehmannAbstract:Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases impeding DNA synthesis. In contrast, nucleoside analogues are much less explored as antibacterial drugs. Thymidine Monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), which is essential to DNA replication, was selected as a promising target for the design of new inhibitors. This review describes stepwise modifications of the TMPKmt substrate, guided by the feedback of enzyme assays and crystallographic analysis to afford potent enzyme inhibitors some of which also exhibited antitubercular activity. More importantly, several of the reported Thymidine analogues provided a deeper understanding of the structure and catalytic mechanism of this intriguing enzyme.
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Substituted benzyl-pyrimidines targeting Thymidine Monophosphate kinase of Mycobacterium tuberculosis: Synthesis and in vitro anti-mycobacterial activity.
Bioorganic and Medicinal Chemistry, 2008Co-Authors: Cécile Gasse, Hélène Munier-lehmann, Dominique Douguet, Valérie Huteau, Gilles Marchal, Sylvie PochetAbstract:A series of N(1)-(4-substituted-benzyl)-pyrimidines were synthesized as potential inhibitors of Thymidine Monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). Key SAR parameters included the chain length substitution in para position of the benzyl ring, the functional group terminating the alkyl chain, and the substituent on the C-5 pyrimidine ring. Synthesized molecules were assayed against both recombinant enzyme and mycobacteria cultures. The most potent compounds have K(i) values in the micromolar range and an MIC(50) of 50microg/mL against Mycobacterium bovis. These results will guide the design of a new generation of lead compounds.
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a new family of inhibitors of mycobacterium tuberculosis Thymidine Monophosphate kinase
ChemInform, 2008Co-Authors: Cécile Gasse, Helene Munierlehmann, Dominique Douguet, Valérie Huteau, Sylvie PochetAbstract:Tuberculosis (TB) ranks among the leading causes of death worldwide from a single infectious agent, particularly in developing countries. The emergence of multidrug resistant strains of Mycobacteri...
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Thymidine and Thymidine 5 o Monophosphate analogues as inhibitors of mycobacterium tuberculosis thymidylate kinase
Bioorganic & Medicinal Chemistry Letters, 2003Co-Authors: Veerle Vanheusden, Piet Herdewijn, Helene Munierlehmann, Sylvie Pochet, Philippe Van Rompaey, Serge Van CalenberghAbstract:The affinity of a series of 2', 3'- and 5-modified Thymidine analogues for Mycobacterium tuberculosis Thymidine Monophosphate kinase (TMPKmt) was evaluated. The affinities of several non-phosphorylated analogues are in the same order of magnitude as those of their phosphorylated congeners. In view of drug delivery problems associated with phosphorylated compounds, these 'free' nucleosides seem more promising leads in the search of TMPKmt inhibitors as novel anti-tuberculosis agents.
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Comparative study of purine and pyrimidine nucleoside analogues acting on the thymidylate kinases of Mycobacterium tuberculosis and of humans.
ChemBioChem, 2003Co-Authors: Sylvie Pochet, Laurence Dugue, Gilles Labesse, Muriel Delepierre, Hélène Munier-lehmannAbstract:Thymidine Monophosphate kinase (TMPK) from Mycobacterium tuberculosis (TMPKmt) is an attractive target for the design of specific inhibitors. This fact is the result of its key role in the Thymidine pathway and of unique structural features in the active site observed by X-ray crystallography, especially in comparison to its human counterpart (TMPKh). Different 5-modified Thymidine derivatives, as well as purine and pyrimidine analogues or C-nucleosides were tested on TMPKmt and TMPKh, and the results were rationalized by docking studies. 5-Halogenated 2'-deoxyuridines are the best inhibitors of TMPKmt found and present the highest selectivity indexes in favor of TMPKmt.